Reduced pulmonary surfactant is integral to the development of respiratory distress syndrome (RDS) and viral infections of premature infants. Respiratory surfactant is composed of a mixture of phospholipids and surfactant-associated proteins designated A-D (SP-A, SP-B, SP-C, SP-D, respectively). SP-A and SP-D are lectins that play an important role in pulmonary defense against pathogens and in modulation of the immune response. Respiratory syncytial virus (RSV) infection is the most common cause of respiratory disease leading to hospitalization in children, especially preterm and young neonates, and is often associated with reduced surfactant protein expression and enhanced tumor necrosis factor-alpha (TNF-alpha) expression. [unreadable] [unreadable] TNF-alpha is an inflammatory cytokine that can be beneficial, but not essential, for RSV clearance. In severe RSV infection; however, the enhanced TNF-alpha expression may detrimentally affect the lung in several ways including inhibition of surfactant protein expression. Recently, the mechanism for TNF-alpha inhibition of SP-A expression was determined to be through the activation of p38 mitogen activated protein kinase (MAPK). Vascular endothelial growth factor (VEGF) can antagonize the cellular effects of TNF-alpha through inhibition of p38 MAPK and is also a growth factor that regulates angiogenesis, maturation of respiratory epithelium, and surfactant synthesis. It is our hypothesis that: VEGF regulates SP-A and SP-D expression and is therapeutically beneficial in conditions with reduced SP-A and SP-D expression including: 1) surfactant production in preterm and young neonates, and 2) severe neonatal RSV infection. [unreadable] [unreadable] The work in this proposal will quantify and define 1) SP-A and SP-D region specific respiratory expression during fetal and neonatal development 2) VEGF alteration of SP-A and SP-D expression in young neonatal lambs; 3) the alteration in RSV disease severity by VEGF or surfactant protein administration; and 4) the role of p38 MAPK in VEGF and TNF-alpha regulation of SP-A. Results of this work will: 1) determine the extent to which a safe and novel treatment (VEGF) can be used as an alternative to glucocorticoids for neonatal infants at risk for RDS; 2) determine the effectiveness of (VEGF) therapy for the reduction in severity of RSV infection in infants; and 3) define pathways (p38 MAPK) for future pharmaceutical intervention in the prevention of severe RSV infection. [unreadable] [unreadable]